10, 11-dihydro-5h-dibenzo[a, d]cycloheptenes as local anesthetics



United States Patent 3,376,192 10,1l DIHYDRO-SH-DHBENZOM,d]CYCLOHEP- TENES AS LOCAL ANESTHETICS Paul 'Greengard, New York, N.Y., assignor to Geigy Chemical Corporation, Ardsley, N.Y., a corporation of New York No Drawing. Continuation-impart of application Ser. No. 267,324, Mar. 12, 1963. This application Oct. 22, 1965, Ser. No. 502,303

11 Claims. (Cl. 167-52) This application is a continuation-in-part of application, Ser. No. 267,324, filed Mar. 12, 1963, now abandoned.

This invention relates to a process for obtaining a local anesthetic effect by administering to a host requiring local anesthesia certain derivatives of 10,11-dihydro-H- dibenzo[a,d]cyclo'heptene (or dib-enzo[a,d]cycloheptal, 4-diene) and their acid addition and quaternary ammonium salts, and to compositions useful for this purpose.

More specifically, the process described employs certain esters and amides of 10, 1l-dihyd-ro-SH-dibenzo[a,d]- cycloheptene-S-carboxylic acid which can be represented by the following structural formula:

H COR wherein X is hydrogen or halogen, particularly, chlorine or bromine R represents N-(loweryalkyl N hydroxy(lower)al'kylamino or the moieties OZ or NHZ in which Z stands for (lower) alkylamin-o(lower)alkyl, di(lower)- alkylamino(lower)alkyl, 1-piperidyl(lower)alkyl and :3-(N-methylpiperidyl) and the pharmaceutically acceptable acid addition salts and quaternary ammonium salts thereof.

The term lower alkyl as used herein means saturated monovalent aliphatic radicals of the general formula mH2m+1 wherein m designates an integer of less than 5 and is inclusive of both straight chain and branched chain radicals.

Representative compounds within the scope of the above formula which have been found to possess local anesthetic properties to a favorable degree are particularly the following:

Z-dimethylaminoethyl 10, l-l-dihydro-SH-dibenzo- [ad] cycloheptene-S-carb oxylate hydrochloride, Z-diethylaminoethyl 10,1 1-dihydrc-5H-dibenzo- ['a,d] cycloheptene-S-carboxylate hydrochloride, 3-diethylaminopropyl l0, ll-dihydro-SH-dibenzm [a,d] cyclohepteue-S-carb oxylate hydrochloride, 2-dimethylaminoethyl 3-chloro-10,1 1-dihydro-5H- dibenzo[a,d] cycloheptene-S-carboxylate hydrochloride, Z-methylaminoethyl 10,ll-dihydro-SH-dibenzm [a d] cycloheptene-S-carboxylate hydrochloride, 2-(l 0,ll1-dihydro-5H-dibenzo [a,d] cycloheptene5- .carboxy) ethyldiethylmethylamrn-onium iodide, 2-(10,1l-dihydro-SH dibenzo[a,d]cycl-oheptene-S- carboxy) ethyldimethylo ctylammonium bromide, 2- 1 pip eridyl-e thyl l 0, 1 1 dihydro-SH-dibenzm [a, d] cycloheptene-S-carboxylate hydro chloride, N-methyl 3 piperidyl 3-chloro-1 0, 11 -5 H-dibenzo- [a,d] cyclohep tene-S-carboxylate hydro chloride, N-ethyl-N- Z-hydroxyethyl -10, 1 l-dihydro-SH-dibenzo- [-a,d]cycloheptene-S-carboxamide, N-Q-(diethylaminoethyl)-.l 0,1 l-dihydro-SH-dibenzo- [*a,d] cycloheptene-S-carb oxamide hydrochloride.

The compounds defined by the above formula can be made by the following modes of preparation:

S-carboxylate derivatives can be formed by refluxing =10,1*1 dihydro-SH-dibenzo-[a,d] cycloheptene-S-carboxylic acid with a basically substituted lower 'alkyl halide in a lower alkanolic medium furnished, e.g. by methanol, ethanol, propanol, etc., from about 2 hours to about 20 hours and preferably, for about 12 hours.

Alternatively, such S-carboxylate derivatives are prepared by refluxing a 10,1 1-dihydro-5=H-dibenzo[a,d]- cycloheptene-S-carboxylic acid halide with a basically substituted lower alkanol in a reaction medium such as is provided by benzene, chloroform, carbon tetrachloride, carbon disulfide, etc. for from about 1 hour to about 2-0 hours and preferably for about 2 hours.

S-carboxylate derivatives of Formula I wherein R is mono(lower)alkylamino(lower)alkyl may be prepared, for instance, by dealkylation of the corresponding di- (lower) alkylaminoflower) alkyl as for example, 'by treatment with ethyl chlorocarbonate to form a urethane derivative which upon saponification gives the desired dealkylated compound.

Alternatively, treatment of an acid halide as mentioned above, with a secondary amino(lower) alkanol in a reaction medium constituted by such solvents as benzene, chloroform, carbon tetrachloride, carbon disulfide, etc. lasting for from about 1 hour to about :20 hours and preferably for about 4 hours, yields an N-*(lower) alkyl-N- hydroxy-(lower) alkyl 10,11 dihydro-5H-dibenzo[a,d]- cycloheptene-S-carboxamide which is also encompassed by the above formula and which when subjected to concentrated hydrochloric acid can be converted to the mono (lower) alkylamino (lower)'alkyl esters.

S-carboxarnide derivatives are made by refluxing the carboxylic acid halides, mentioned above, with an appropriately substituted lower alkylene diamine, in a reaction medium exemplified by benzene, chloroform, carbon tetrachloride, carbon disulfide, etc. for about 1 hour to about 20 hours and preferably about 2 hours.

The starting materials are either commercially available, as for example, the above mentioned alkyl halides and alkanols or, as in the case of the above identified 5- carboxylic acid and S-carboxylic acid halide derivatives, can be readily prepared in accordance with well known prior art syntheses.

The present invention comprehends not only the above described derivatives of 10,1ldihydro-SH-dibenzo[a,'d]- cycloheptene in their free base form, but it also includes pharmaceutically acceptable non-toxic acid addition salts which may be formed from said compounds in accordance with conventional practice, by using appropriate inorganic and organic acids, such as hydrohalic acids, especially hydrochloric and hydrobrornic acids, sulfuric, ethanesulfonic and phosphoric acids as well as acetic, aminoacetic, lactic, succinic, malic, aconitic, phthalic, tartaric acids, etc.

The pharmaceutically acceptable quaternary ammonium salts of compounds of the present invention, can be obtained by addition to the corresponding free bases of alkyl or aralkyl esters of inorganic sulfonic acids, including such compounds as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, propyl bromide, octyl bromide, benzyl chloride, benzyl bromide, methyl sulfate, methyl benzenesulfonate, and methyl p-toluenesulfonate, giving the methochloride, methobromide, methoiodide, ethobromide, propobromide, octobromide, benzochloride, benzobromide, methosulfate, methobenzenesulfonate, and metho-p-toluene sulfonate salts, respectively.

The methods for the preparation of these compounds can be exemplified more fully by the following illustrative examples. The temperatures therein are given in degrees centigrade.

Example 1.--2-dimethyl 10,11-dihydro-H-dibenzo[a,d] cycloheptene-S-carboxylate hydrochloride 10,11 dihydro 5H dibenzo[a,d]cycloheptene 5- carboxylic acid (11.9 g., 0.05 mole) was dissolved in 200 ml. of benzene. To the solution was added 50 ml. of thionyl chloride. The mixture was refluxed for 18 hours and then concentrated in vacuo to an oily residue which was taken up in benzene and again concentrated to a syrup. The syrup was dissolved in 100 ml. of benzene and 4.4 g. (0.05 mole) of dimethyl-arninoethanol in 50 ml. of benzene was added dropwise at room temperature. The reaction was stirred and refluxed for 4 hours. The reaction mixture was cooled and the desired compound was filtered oil as white crystals. After recrystallization from ethanol it melted at 210-2128. Yield: 7 g.

Analysis for C H ClNO Calcd C, 69.47; H, 6.99; N, 4.05. Found C, 69.39; H, 7.04; N, 4.08.

Example 2.-2-diethylaminoethyl 10,l1-dihydro-5H-dibenzo[a,d] cycloheptene-5-carboxylate hydrochloride 10,11 dihydro 5H dibenzo[a,d]cycloheptene 5- carboxylic acid (10.70 g., 0.045 mole) and 6.10 g. (0.045 mole) of Z-diethylaminoethyl chloride in 90 ml. of dry isopropanol were heated to reflux for 12 hours. Upon cooling in ice the reaction product (16.47 g.) precipitated. After recrystallization from the same solvent and washing with absolute ether and drying, the desired compound melted at 195-197, 'yKBr C=O 1740 cmr Analysis for C H ClNO Calcd C, 70.66; H, 7.56; N, 3.75. Found C, 70.35; H, 7.77;N, 3.49.

Example 3.-3-diethylaminopropyl 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-S-carboxylate hydrochloride This compound was prepared in accordance with the method described in Example 1 using 8 g., (0.033 mole) of carboxylic acid and 4 g. (0.033 mole) of 3-diethylamino-1-propano1;M.P. 147-148"; yield 3.5 g.

Example 4.-2 dimethylaminoethyl 3 chloro 10,11- dihydro 5H dibenzo[a,d]cycloheptene 5 carboxylate hydrochloride Using 13.5 g. (0.05 mole) of 3-chloro-10,11-dihydro- 5H-dibenzo[a,d]cycloheptene-S-carboxylic acid and 4.4 g. (0.05 mole) of dimethylaminoethanol, g. of this compound were prepared, M.P. 215-216, in accordance with the method given in Example 1.

Example 5 .2 methylaminoethyl 10,11 dihydro 5H- dibenzo[a,d] cycloheptene-S-carboxylate hydrochloride monohydrate 10,11 dihydro 5H dibenzo[a,d]cycloheptene 5- carboxylic acid (6 g., 0.024 mole) were dissolved in 80 cc. of benzene and treated with 10 cc. of thionyl chloride. The mixture was refluxed for 18 hours and concentrated to a syrupy residue which was taken up in benzene and again concentrated to a syrup. The syrup was dissolved in 50 cc. of benzene and 3.9 g. of 2-methylaminoethanol in 20 cc. of benzene was added at 5. The reaction mixture was stirred and refluxed for 6 hours. The reaction mixture was cooled and 100 cc. of water wasadded. The benzene layer was separated and dried over Na SO The reaction mixture was filtered and after concentration an oil was obtained. It was N-methyl-N-(2-hydroxyethyl)- 10,11 dihydro 5H dibenzo[a,d] cycloheptene 5 carboxamide, which was suspended in 2 g. of concentrated hydrochloric acid. The mixture was warmed at 80 for 30 minutes, cooled and diluted with 60 cc. of ethanol. The mixture was then concentrated in vacuo and an oil was obtained upon cooling which crystallized out. After recrystallization from a mixture of ethyl acetate and isopropanol, 921, 0.5 g. of the desired compound was obtained; M.P. 170-171".

Analysis for C H ClNO Calcd C, 65.32; H, 6.92; N, 4.00. Found C, 65.63; H, 7.04; N, 3.83.

4- Example 6.2 (10,11 dihydro 5H dibenzo[a,d] cycloheptene 5 carboxy) ethyldiethylmethylammonium iodide The compound of Example'Z (7.90 g., 0.21 mole) was dissolved in 25 ml. 2 N ice cold NaOH and extracted thrice with 100 ml. of ether. The combined extracts were dried over K CO evaporated to 50 ml. and treated dropwise with 3.12 ml. (0.05 mole) freshly distilled methyl iodide in 50 ml. of absolute ether at 0 undervigorous stirring. The resulting precipitate, 7.89 g. of white crystals was filtered and recrystallized from acetone and ether, M.P. 156-158", yKBr C O 1740 emu- Analysis for C H INO Calcd C, 57.70; H, 6.31; N, 2.92. Found C, 57.68; H, 6.46; N, 2.82.

Example 7.-2 (10,11 dihydro 5H dibenzo[a,d] j

extract gave 4g. of 2-dimethylaminoethyl 10,11-dihydro 5I-I-dib enzo [a,d] cycloheptene-S-carb oxylate.

Z-dimethylaminoethyl 10,1 1-dihydro-5l-l-dibenzo[a,d]-

cycloheptene-S-carboxylate (4 g.) was dissolved in 100 ml. of dry acetone. To the solution was added the equivalent amount of octyl bromide (2.8 g). The mixture was refluxed for 28 hours and then concentrated. The oily residue that was obtained crystallized on addition of ether (cooling). After recrystallization from a mixture of ethyl acetate and ether, the desired ammonium 85-87; yield 2.5 g.

Analysis for C H BrNO Calcd C, 66.95; H, 8.19; N, 2.78. Found C, 67.24; H, 8.21; N, 3.01.

Example 8.-2-( l-piperidylethyl)-10,1l-dihydr.o 5H dibenzo[a,d] cycloheptene 5 carboxylate hydrochloride monohydrate By following the procedure of Example 1 and using (4 gm, 0.016 mole) of the carboxylic acid and 3.8 g. (twice amount) of N-Z-hydroxyethyl piperidine 0.7 g. of the desired compound, M.P. 104-105 was obtained.

Example 9.N-methyl-3-piperidyl 3-ch1oro-10,11 dihydro-SI-I-dibenzo[a,d]cycloheptene-S-carboxylate hydrochloride Using 5.4 g. (0.02 mole) of 3-chloro-10,11-dihydro- 5H-dibenzo[a,d] cycloheptene-5-carboxylic acid and 4.6 g.

of 3-hydroxy-N-methylpiperidine, 3.5 g. of the desired compound, M.P. 249-250, were produced in analogy to above described preparative methods.

Example 10.N-ethyl-N-(Z-hydroxyethyl) 10,11 dihydro-SH-dibenzo [a,d] cycloheptene-S-carhoxamide 10,11-dihydro-5H dibenzo[a.d]cycloheptene 5 carboxylic acid (4 g., 0.016 mole) was dissolved in cc. of

benzene and treated with 10 cc. of thionyl chloride. The

concentrated to a syrup. The syrup was dissolved in 50 cc. of benzene and 2.7 g. (0.032 mole) (twice the amount) of Z-ethylamino ethanol in 20 cc. of benzene was added at room temperature. The reaction mixture was stirredand refluxed for 6 hours. The reaction mixture was cooled and 25 cc. of water was added. The benzene layer was separated and dried over Na SO The reaction mixture was filtered and after concentration an oil was obtained. After recrystallization from ethyl-acetate, it melted. at 114-115 Yield: 1.5 g.

Analysis for C H NO Calcd C, 77.38; H, 7.79; N, 4.51. Found C, 77.15; H, 7.49; N, 4.78.

10 with 10% NaOH and the liberated salt melted at Example 11.N-2- (diethylaminoethyl) 10,11 dihydro- 5H dibenzo[a,d] cycloheptene 5 carboxamide hydrochloride monohydrate 10,11-dihydro-5H dibenzo[a,d]cyc1oheptene 5 carboxylic acid (9.2 g., 0.04 mole) was dissolved in 160 ml. of benzene and treated slowly with ml. of thionyl chloride. The mixture Was refluxed for 18 hours and concentrated to a syrupy residue in vacuo, which was taken up in benzene and again concentrated to a syrup. The syrup was dissolved in 100 ml. of benzene and 4.7 g. (0.04 mole) of N,N-diethylethylenediamine in 500 ml. of benzene were added dropwise at room temperature. The reaction mixture was stirred and refluxed for 4 hours. Upon cooling crystals separated, which, afte recrystallization from a mixture of isopropanol and ethanol (8:2) melted at 133135; yield 6.7 g.

Analysis for C H ClN O Calcd C, 67.76; H, 8.00; N, 7.16. Found C, 67.79; H, 8.35; N, 7.00.

As mentioned above, the compounds described herein can be employed to produce a local anesthetic effect in a host-animals or humansrequiring anesthesia. Local anesthetic activity can be determined by infiltration and conduction anesthesia experiments.

Infiltration anesthesia (guinea pig wheals) experiments are conducted as follows:

By pricking the dorsal skin of a shaved guinea pig with a pin, a contraction of the muscle is obtained; this serves as a stimulus and response for testing compounds injected intradermally. A volume of 0.25 ml. of test solution is injected. Six one-inch wheals are made on each animal, three on a side parallel with the spinal column. The wheals are circled with ink and pricked at 5-minute intervals to determine duration of eifect. The minimal concentration that produces anesthesia Without irritation is determined. Saline controls are used. Reference drugs are: Procaine (in saline) 20 min-90 min. (0.5% )-no irritation; dibucaine (in saline) 15 min-120 min. (0.25 no irritation; lidocaine, 15 min.95 min. (2% )no irritation.

Conduction anesthesia can be determined by using the sciatic nerve block test in mice. The procedure is as follows: 3 male mice, weighing 18-22 g, are used for each compound, per dose level with varying concentrations. (Volume administered is always 0.05 cc.). A sharp 27 gauge, /z-inch hypodermic needle is used. A landmark. for the entrance of the needle is the trochanter of the femur, and the level of the needle should face the vertebral column. The needle is inserted in such a manner as to be virtually in contact with the sciatic nerve. Before the injection, which is given rapidly, the leg is held in a lightly stretched position; upon completion of the injection the tipv of the index finger is pressed over the injection site and the pressure is maintained for approximately five to ten seconds. The mice become paddle-footed and the toes cupped. Depending upon the intensity of anesthesia, the foot may become inverted. The ipsilateral flexor reflex may be lost. The mice lose their grip in the treated leg and there is no pain response to light pinching of the muscle in and radiating from the injected area. Onset and duration of anesthesia are noted and compared with a standard which is lidocaine HCl:

The results obtained are summarized in the following tables in an illustrative and comparative manner:

In Minutes Compound Concentration Onset Duration Example 1 1 3 105 Do. 3 120 D0- 3 120 Do 3 30-fi0 Lidocaine HCL. 3 xample 3 3 Lidocaine HCl. 3 75 Example 4 10 120 Lidocaine HCL- 3 75 x ple 3 90 Lidocaine HCl 3 75 Example 6 3 75 Doa 3 90 Lidocainc HCL. 3 75 Example 8 3 90 Do 3 90 Lidocaine HCl 3 75 Example 9 9 45 Lidocaine HCL; 3 45 Example 10 12 75 Lidocaine H01 3 90 Example 11 3 75 Lidocaine H01 3 90 TABLE II.CONDUCTION ANESTHESIA (SCIATIC NERVE BLOCK) In Minutes Compound Concentration Onset Duration Example 1 1 1% M6 Lidocaine HCl 1%... M6... 27% Example 1 0.1% 28 Lidocaine HCl 0.1%- V 17 Example 1 0.1%. la. 29% Lidocaine HCl 0.1%; 14 Example 1 0.05%. yl64: 24 Do 0.005% M6. 2 Do... 0.05%. M16. 18 Lidocaine HC1 0.05%-" Mfi- 9 Example 1 0.0075% M6 29 Lidocaine HCl 1% M6 36 Example 1 1 V1 243 0 20 Lidocainc H01- 8 Example 2." 300 Lidocaine H01. lg U 269 6 26 120 29 27 480 1 This compound seems to produce more widespread anesthesia than lidocaine HOl at same dose. H CDegIee of anesthesia is greater with this compound than with lidocaine Onset of potent" action is more delayed than with lidocaine H01, however, anesthetic eficct is longer lasting.

From the above tables it will -be seen that the compound of Example 1, for instance, has the same speed of onset of action as lidocaine, is more potent than lidocaine and has considerable longer duration of action than lidocaine. A number of the other subject compounds also compare favorably with lidocaine.

The compounds useful in practicing this invention are relatively non-toxic and therefore compatible with their intended use as local anesthetics. For example, the compound of Example 1 has an LD i.p. in mice of mg./kg. and its LD i.v.in mice is 36 mg./kg., while the corresponding data for lidocaine are: mg/kg. i.p. and 20'mg./kg. i.v.

The anesthetics of the invention can be administered by any of the conventional means available for use in conjunction with pharmaceuticals. They preferably are used in the form of a composition comprising a vehicle such as an organic solvent. Such compositions include sterile solutions for irrigation, subcutaneus injection, and dispersions of the compounds in an oil emulsion, jelly, ointment, or cream base, or aerosols either alone or in combination with other therapeutic agents, such as, antihistamines, sulfa drugs and antibiotics. All such are included herein in the term vehicle.

The concentration of the active ingredient in the pharmaceutical composition can be varied as desired to meet the need. The concentration will depend in part upon the amount of the compositions that is conveniently administered. A lesser amount of a sterile solution would be administered subcutaneously than might be applied topically in the form of an oil, emulsion, jelly, ointment, cream or aerosols. In most cases, concentrations ranging from 0.001% to about by weight will be quite adequate.

Useful pharmaceutical formulations for administration of the compounds of the invention are as follows:

Formula A.Solution for subcutaneous administration Component: Percent Active ingredient 1 Benzyl alcohol 0.9 Water for injection, q.s.

Formula B Gelled composition:

Active ingredient 1 Metuocel 4.25 Propylene glycol Distilled water, q.s.

Formula C Cream:

Active ingredient 1 Propylene glycol 57 Carbowax 6000 42 The compounds of the invention can also be employed in the form of troches and lozenges, and they can be dispensed as dry powders suitable for admixing in pharmaceutical carrier immediately prior to administartion.

When used for the treatment of mucous membrane anesthesia, the active ingredient is best incorporated in an aqueous spray. This spray is prepared by dissolving the compound in an aqueous medium, bringing the pH to within the range of about 6.5 to about 7.2, preferably 6.7 to 7.1, with a base such as alkali metal hydroxide, for example sodium hydroxide. Effective anesthesia is obtained with a concentration as low as 0.5% (w./v.), but it is usually preferably to employ somewhat more, within the range from about 1% to about 5%. Preserves such as combinations of methyl paraben, ethyl paraben, propyl paraben can also be incorporated.

What is claimed is:

1. A process for locally anesthetizing which comprises administering to an animal and human host requiring local anesthesia a compound of the formula H COR wherein 3. A process in accordance with claim 1 in which the 1 compound is 2-(10,1l-dihydro-SH-dibenzo[a,d]cycloheptene-S-carboxy)ethyldimethyloctylammonium bromide.

4. A process in accordance with claim 1 inwhich the, 1 compound is 2-(10,11dihydro-5Hdibenzo[a,d]cycloheptene-S-carboxy)ethyldiethylmethylammonium iodide.

5. A process in accordance with claim 1 in which the compound is Z-dimethylaminoethyl 3-chloro-10,l1-dihydro SH-dibenzo[a,d]cycloheptene-S-carboxylate hydrochloride.

6. A process in accordance with claim 1 in which the compound is N-rnethyl-3-piperidyl 3-chl0ro-10,l1-dihydro SH-dibenzo[a,d]cycloheptene-5-carboxylate hydrochloride.

7. A process in accordance with claim 1 in which the compound is N-Z-(diethylaminoethyl)-l0,ll-dihydro-SH- dibenzo [a,d] cycloheptene-S-carboxamide hydrochloride.

8. A process in accordance with claim 1 in which the compound is 2-(l-piperidylethyl) 10,1l-dihydro-5H-dibenzo [a,d] cycloheptene-S-carboxylate hydrochloride.

'9. A process is accordance with claim 1 in which the compound is S-diethylaminopropyl 10,1l-dihydro-5I-I-dibenzo [a,d] cycloheptene-S-carboxylate hydrochloride.

10. A process in accordance with claim 1 in which the compound is 2-rnethylaminoethyl 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-Scarboxylate hydrochloride.

11. A process for locally anesthetizing which comprises administering to an animal host requiring local anesthesia a compound selected from the group consisting of esters and amides having the formula wherein and pharmaceutically.acceptable quaternary ammonium salts thereof.

References Cited UNITED STATES PATENTS 9/1966 Renault "167-52 12/1966 Thesing 16752 ALBERT T. MEYERS, PrimaryExaminer.

JULIAN S. LEV] l'l, SAM ROSEN, Examiners.

JEROME D. GOLDBERG, Assistant Examiner. 

1. A PROCESS FOR LOCALLY ANESTHETIZING WHICH COMPRISES ADMINISTERING TO AN ANIMAL AND HUMAN HOST REQUIRING LOCAL ANESTHESI A COMPOUND OF THE FORMULA 